The clinical management of critical (>3cm) defects in bone from traumatic injuries remains a major challenge for both amputation and limb salvage cases. Thus, the quest for a practical adjuvant therapy, such as teriparatide (PTH{1-34}), remains a high priority. Despite extensive work concluding that PTH{1-34} is effective in small animal models of fracture healing, success in translating this technology into a human therapy remains elusive. To this end we have made remarkable progress during the initial funding period of this CORT by developing a computerized tomography (CT) outcome measure (Union Ratio) that correlates with torsional biomechanics; and clinical cone beam (CB) CT with metal artifact suppression to quantify massive allograft healing in dogs and humans. Now we propose to perform a definitive large animal study (canine femoral defect), with translational outcome measures to formally establish PTH{1-34} efficacy in a clinically relevant model of challenging bone healing. Two cohorts of skeletally mature dogs will be studied to evaluate PTH{1-34} effects on femoral allograft healing. In Aim 1 the dogs will be randomized to placebo or PTH{1-34} treatments, followed by longitudinal CB-CT, and sacrificed at 8-weeks or 6-months to assess eariy and mature allograft healing. The primary outcome will establish PTH{1-34} effects on ex vivo torsional biomechanics (stiffness and torque to failure), and the secondary outcomes, including histomorphometry. will establish PTH{1-34} effects on in vivo radiology (Union Ratio and bone volume). In Aim 2 we will use these data to demonstrate that the Union Ratio correlates significantly with fracture healing (torsional biomechanics) compared to the current clinical standard of subjective x-ray scoring. Finally, in Aim 3 we will complete the ongoing clinical pilot of the natural history of human massive allograft healing determined by CB-CT at 0.5, 8 and 18-months. Union Ratios will be quantified from these data to derive a power calculation for a PTH{1-34} efficacy clinical trial in limb salvage patients.